After 20 Years, A Drug That Silences Genes Succeeds

Winners of the 2006 Nobel Prize in Medicine for their discovery of RNAi Andrew Z.Fire (L) and Craig C. Mello pose during a press conference in December 2006, at the Karolinska Institute in Stockholm. (Photo by SVEN NACKSTRAND/AFP/Getty Images)

After two decades, a laboratory breakthrough that upended scientists’ understanding of how genes work looks set to yield a treatment for a rare hereditary disease – and maybe a whole new type of drug.

Shares in Alnylam Pharmaceuticals rocketed up 40% to $105 in morning trading after the company announced that a 227-patient study showed its drug patisiran showed real benefits in the treatment of hereditary ATTR amyloidosis with polyneuropathy, a rare disorder that causes patients to lose their ability to dress themselves, use utensils, or walk. Patients usually die within 15 years of diagnosis.

Patients who received patisiran did better than those who received placebo on both a modified neuropathy impairment score and a quality of life questionnaire. Alnylam did not release specific figures when it announced the results via press release. Deaths occurred in 4.7% of the patients who received patisiran, compared to 7.8% of those who received placebo, although Alnylam called those numbers “similar,” meaning they were not statistically different. In a particularly striking finding, 37.7% of the patients on placebo stopped treatment, compared to 7.4% on patisiran, a sign that the drug likely is making a difference. The drug is being co-developed with Sanofi, the French drug giant.

Analyst Paul Matteis at Leerink Research gushed in a note to clients that the results represent a “best case.” Analyst Alethia Young at Credit Suisse notes that the potential for the drug could be even bigger if the drug also shows potential in patients who have a similar condition that affects their hearts. Full results will be presented at a medical meeting on November 3.

The story of Alnylam is an object lesson in how long it can take to turn a scientific innovation into a medicine. In 1998, Craig Mello and Andrew Fire, professors at the University of Massachusetts and the Carnegie Institution, published a stunning finding: in some cases, genes worked completely differently from the way scientists had thought. The central dogma of biology is that genes, made of DNA, are turned into chemical messengers called RNA that then are turned into proteins, the building blocks of living things. Mello and Fire found that in some cases, DNA makes a different kind of RNA, called RNAi, that tricks cells into destroying messenger RNA before it can be used to make a protein. In essence, RNAi blocks the gene.

Most drugs work by blocking or replacing proteins. Being able to do this at the genetic level was exciting, and Alnylam was founded in 2002 to make this a reality. (See this story from 2003.) In 2006, Mello and Fire were awarded the Nobel Prize in Medicine. But making a medicine was far away. The key problem was how to get RNAi, which breaks down if it’s just injected into the bloodstream, into cells. In 2012, Alnylam agreed to pay $65 million to another company, Arbutus, for technology it uses to make its drugs. If patisiran reaches the market, which now looks likely, Arbutus will get an undisclosed royalty on sales.

Investors had butterflies right up to this moment, not so much wondering whether the drug would be effective but whether some side effect would creep up. Last fall, a drug called revusiran was discontinued because of an imbalance in deaths from heart disease in a clinical trial. Earlier this month, testing of a hemophilia drug called fitusiran was stopped temporarily after a patient died from a clot.

There’s competition in amyloidosis. Shares in Ionis, which has a technology that works on DNA in a different way and is developing a different drug, is down 8% on Alnylam’s results. But the big question is whether RNAi can work in other rare diseases – or even in common ones. Alnylam is developing a twice-a-year RNAi cholesterol drug with The Medicines Company.

It’s been 20 years since Mello and Fire first told us about RNAi. Now, it finally works as a way to make a drug.

From June 5, 2000, until December 21, 2018, I covered science and medicine for Forbes. That took me from the Human Genome Project through Vioxx to the blossoming DNA technology changing the world today. It was an amazing run.